Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1 (STR1VE)

Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies Delivering AVXS-101 by Intravenous Infusion

Phase 3 pivotal US trial studying open-label intravenous administration of onasemnogene abeparvovec-xioi in spinal muscular atrophy (SMA) Type 1 participants.

Study Overview

• Status: Completed
• Conditions: Gene Therapy; SMA - Spinal Muscular Atrophy
• Intervention / Treatment: Biological: Onasemnogene Abeparvovec-xioi

Detailed Description

Phase 3, open-label, single-arm, single-dose, study of onasemnogene abeparvovec-xioi (gene replacement therapy) in participants with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria and are genetically defined by nonfunctional survival motor neuron 1 gene (SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2). Fifteen (15) participants < 6 months (< 180 days) of age at the time of gene replacement therapy (Day 1) will be enrolled.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Orlando, Florida, United States, 32827
      • Nemours Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H Lurie Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Pediatric Neurology
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington Unviersity School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • North Carolina
    • Durham, North Carolina, United States, 27713
      • Duke University
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin (Madison)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 5 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants with SMA Type 1 as determined by the following features: a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier mutation (c.859G>C))2
• The first 3 participants enrolled must meet the criteria for the Intent-To-Treat Population
• Participants must be < 6 months (< 180 days) of age at the time of onasemnogene abeparvovec-xioi infusion
• Participants must have a swallowing evaluation test performed prior to administration of gene replacement therapy
• Up-to-date on childhood vaccinations. Seasonal vaccinations that include palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended in accordance with American Academy of Pediatrics
• Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with study procedures and visit schedule

Exclusion Criteria:

• Previous, planned or expected scoliosis repair surgery/procedure during the study assessment period
• Pulse oximetry < 96% saturation at screening while the participant is awake or asleep without any supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation < 92% awake or asleep without any supplemental oxygen or respiratory support Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation does not decrease by ≥ 4 percentage points
• Tracheostomy or current use or requirement of non-invasive ventilatory support averaging ≥ 6 hours daily over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during the screening period or requiring ventilatory support while awake over the 7 days prior to screening or at any point during the screening period prior to dosing
• Participants with signs of aspiration/inability to tolerate non-thickened- liquids based on a formal swallowing test performed as part of screening. Participants with a gastrostomy tube who pass the swallowing test will be allowed to enroll in the study
• Participants whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards
• Active viral infection (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C, or Zika virus)
• Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 2 weeks prior to screening
• Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 weeks prior to screening
• Severe non-pulmonary/respiratory tract infection within 4 weeks before administration of gene replacement therapy or concomitant illness that creates unnecessary risks for gene replacement therapy such as: a. Major renal or hepatic impairment b. Known seizure disorder c. Diabetes mellitus d. Idiopathic hypocalcuria e. Symptomatic cardiomyopathy
• Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
• Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 3 months prior to gene replacement therapy
• Anti-adeno-associated virus serotype 9 (AAV9) antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay. Should a potential participant demonstrate Anti-AAV9 antibody titer > 1:50, he or she may receive retesting within 30 days of the screening period and will be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50
• Clinically significant abnormal laboratory values (gamma glutamyl- transpeptidase [GGT], ALT, and AST > 3 × ULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy
• Participation in recent SMA treatment clinical study (with the exception of observational Cohort studies or non-interventional studies) or receipt of an investigational or commercial compound, product, or therapy administered with the intent to treat SMA at any time prior to screening for this study. Oral β-agonists must be discontinued at least 30 days before gene therapy dosing. Inhaled albuterol specifically prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not a contraindication at any time prior to screening for this study
• Expectation of major surgical procedures during the study assessment period
• Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability to travel for repeat visits
• Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to refrain from posting confidential study results/observations on social media sites
• Parent(s)/legal guardian(s) refuses to sign consent form
• Gestational age at birth < 35 weeks (245 days)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Onasemnogene Abeparvovec-xioi; One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.

Biological: Onasemnogene Abeparvovec-xioi; Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.; Other Names: Zolgensma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Achievement of Independent Sitting for at Least 30 Seconds	Independent sitting is defined as sitting up straight with head erect for at least 30 seconds. This endpoint is a co-primary endpoint. The two co-primary efficacy endpoints were assessed in sequence: The endpoint of functional independent sitting was assessed first and, only when this assessment met statistical significance, was the endpoint of event-free survival assessed.	Up to 18 months
Event-free Survival	Survival is defined by the avoidance of combined endpoint of either death or permanent ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative ventilation. Permanent ventilation is considered a surrogate for death. An acute reversible illness is defined as any condition other than SMA that results in increased medical intervention. The endpoint is a co-primary endpoint. The two co-primary efficacy endpoints were assessed in sequence: The endpoint of functional independent sitting was assessed first and, only when this assessment met statistical significance was the survival endpoint assessed.	14 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ability to Thrive	Ability to thrive is defined as achieving all of the following at 18 months of age: does not receive nutrition through mechanical support or other non-oral method; ability to tolerate thin liquids as demonstrated through a formal swallowing test; maintains weight This is a co-secondary endpoint. The two co-secondary endpoints were assessed in sequence: The endpoint of ability to thrive was assessed first and, only when this assessment met statistical significance was the endpoint of ventilatory support independence assessed.	18 months
Ventilatory Support Independence	Ventilatory support independence is defined as requiring no daily ventilator support/usage at 18 months of age, excluding acute reversible illness and perioperative ventilation, through assessment of actual usage data captured from the device (Phillips Trilogy BiPAP device). This endpoint is derived solely from the Phillips Trilogy BiPAP device. This is a co-secondary endpoint. The two co-secondary endpoints were assessed in sequence: The endpoint of ability to thrive was assessed first and, only when this assessment met statistical significance was the endpoint of ventilatory support independence assessed.	Up to 18 months

Collaborators and Investigators

• Sponsor: Novartis Gene Therapies

Publications and helpful links

General Publications

• Day JW, Mendell JR, Mercuri E, Finkel RS, Strauss KA, Kleyn A, Tauscher-Wisniewski S, Tukov FF, Reyna SP, Chand DH. Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Drug Saf. 2021 Oct;44(10):1109-1119. doi: 10.1007/s40264-021-01107-6. Epub 2021 Aug 12. Erratum In: Drug Saf. 2022 Feb;45(2):191-192.
• Day JW, Finkel RS, Chiriboga CA, Connolly AM, Crawford TO, Darras BT, Iannaccone ST, Kuntz NL, Pena LDM, Shieh PB, Smith EC, Kwon JM, Zaidman CM, Schultz M, Feltner DE, Tauscher-Wisniewski S, Ouyang H, Chand DH, Sproule DM, Macek TA, Mendell JR. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021 Apr;20(4):284-293. doi: 10.1016/S1474-4422(21)00001-6. Epub 2021 Mar 17.

Helpful Links

• Recruitment Website
• sponsor company website
• Novartis Results Record

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2017
• Primary Completion (Actual): November 12, 2019
• Study Completion (Actual): November 12, 2019

Study Registration Dates

• First Submitted: October 2, 2017
• First Submitted That Met QC Criteria: October 4, 2017
• First Posted (Actual): October 11, 2017

Study Record Updates

• Last Update Posted (Actual): August 16, 2022
• Last Update Submitted That Met QC Criteria: August 12, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal
• Other Study ID Numbers: AVXS-101-CL-303; 2020-000095-38 (EudraCT Number); COAV101A12302 (Other Identifier: Novartis Pharmaceuticals)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No